ABSTRACT Opiate use, dependence, and addiction have dramatically increased to epidemic proportions in recent years. This is a reflection of the increased misuse of prescription opioids and abuse of illegal opiate drugs, such as heroin. Unfortunately, there are still relatively few effective pharmacotherapeutic interventions available for the treatment of substance abuse and addiction, most of which rely on a replacement therapeutic model. Neuronal plasticity is considered to be a substrate that mediates the long-lasting changes in the brain's reward circuit and a key component of the long-term addiction disease state. These neural adaptations occur in brain regions such as the nucleus accumbens and lead to long-term drug craving and drug relapse. Currently, there is a scarcity of mechanistic evidence that explores the molecular mechanisms of heroin-induced structural plasticity. The overarching focus of this proposal is to determine the functional cellular neurobiological mechanisms of heroin-induced behavioral plasticity. The proposed studies investigate the role of actin dynamics mediated through the actin-binding protein drebrin in heroin-induced plasticity, ultimately resulting in long-term drug craving and relapse behaviors. To this end, we have proposed three Specific Aims that will test the following hypotheses: to determine if heroin self- administration results in a persistent and epigenetically-mediated decrease in the actin-stabilizing protein drebrin, which in turn regulates actin turnover (Aim I); to determine that drebrin is an essential molecular mechanism underlying heroin-induced relapse-like behaviors and structural plasticity following abstinence from heroin self-administration (Aim II); and to determine if drebrin mediates drug seeking and structural plasticity in D1- and in D2-expressing medium spiny neurons following heroin self-administration (Aim III). This application presents an opportunity to determine, for the first time, a causal mechanism?drebrin?in the underlying cellular (actin dynamics; D1/D2 MSN cellular specificity), structural (morphological), and behavioral (reinstatement) plasticity induced by heroin. The findings from the work in this application will elucidate mechanisms by which chronic heroin exposure induces long-term changes in the plasticity of nucleus accumbens neurons and provides new directions for the development of novel therapies for heroin addiction.